Surgical aortopulmonary shunt (Blalock–Taussig–Thomas shunt)

Blalock–Taussig–Thomas shunt is a surgical procedure of bridging the subclavian or innominate artery to pulmonary artery, first reported in 1945. ^{Reference Blake and Yancy39} Despite being considered as the sole treatment for patients with tetralogy of Fallot in the past, Blalock-Taussig-Thomas shunt is currently indicated for infants with complex single-ventricle physiology or patients with late presentation. Primary tetralogy of Fallot repair is the definitive management of tetralogy of Fallot, though many centres still palliate infants before the definitive procedures. ^{Reference Kaskinen, Keski-Nisula and Martelius40} Modified Blalock–Taussig–Thomas shunt, originated from the Great Ormond Street Group, is developed from Blalock–Taussig–Thomas shunt by interposing a prosthetic tube between the subclavian artery and pulmonary artery. This technique is more advanced with less dissection compared to the previous technique while guaranteeing a proximal and distal anastomosis of large diameter. The maximal flow is regulated by the patient’s uninterrupted subclavian artery diameter, thus allowing for a possible increase in shunt flow with growth. However, Blalock–Taussig–Thomas shunt has been associated with high morbidity and mortality (10–20%) even with the advancement in technology and technique, thus making transcatheter approach more of an attractive alternative. ^{Reference Kaskinen, Keski-Nisula and Martelius40,Reference Caputo, Mokhtari and Rogers41}

The incidence of pulmonary reperfusion injury in Blalock–Taussig–Thomas shunt varied between studies. Two patients with univentricular heart complex and pulmonary stenosis had pulmonary reperfusion injury after undergoing modified Blalock–Taussig–Thomas shunt using polytetrafluoroethylene tube and classsic Blalock–Taussig–Thomas shunt. ^{Reference Okita, Miki and Kusuhara42} Tassig et al observed that from the 601 patients who survived Blalock–Taussig–Thomas shunt, 20 patients (3.3%) developed pulmonary hypertension. ^{Reference Tassig, Crocetti and Eshaghpour43} Hofschire et al added that incidence of pulmonary vascular disease increased with time following the Blalock–Taussig–Thomas shunt. There was no patient, from total of 36 patients, developed severe pulmonary vascular changes in less than 8 years following the Blalock–Taussig–Thomas shunt, while 10 of 20 patients (50%) developed some degree of pulmonary vascular disease after having Blalock–Taussig–Thomas shunt 8 years or longer. ^{Reference Hofschire, Rosenquist, Ruckerman, Moller and Edwards44}

The mechanism for pulmonary reperfusion injury in Blalock–Taussig–Thomas shunt was thought simply due to overshunting which is depicted by signs of shock and congested lungs with wide pulse pressure from six readings within 6 hours and saturation above 85 on room air. ^{Reference Ismail, Almazmi and Khokhar45} Overshunting might be caused by a bigger shunt size leading to a diastolic run-off which ends up with decreased coronary and systemic perfusion. However, this notion was denied in the study by Ismail et al, which indicated that a larger shunt size did not correlate with overshunting. ^{Reference Ismail, Almazmi and Khokhar45,Reference Dirks, Prêtre and Knirsch46} Degree of shunting or pulmonary flow to systemic flow ratio (Qp:Qs) in Blalock–Taussig–Thomas shunt is also dependent on the ratio of pulmonary to systemic vascular resistance. In case of overshunting, we have to optimise the balance of Qp:Qs by increasing the pulmonary vascular resistance and reducing the systemic vascular resistance. Pulmonary vascular resistance may be increased by reducing fraction of inspired oxygen to 0.21 despite suctioning or nebulising, avoiding hyperventilation with targeted permissive hypercapnea, administering high positive end-expiratory pressure of 6–9, and maintaining blood pH of 7.35–7.40. Systemic vascular resistance may be reduced by administering inodilators. ^{Reference Ismail, Almazmi and Khokhar45,Reference Wardoyo, Makdinata and Wijayanto47}

The long duration of Blalock–Taussig–Thomas shunt procedure is one of the risks of pulmonary reperfusion injury because ischaemia-reperfusion injury of the lungs occurs not only after the procedure but also during the surgical procedure by utilisation of cardiopulmonary bypass. Previous animal studies performed in dogs have shown that cardiopulmonary bypass procedures increase malondialdehyde content in the lung interstitium with simultaneous downregulation of superoxide dismutase activity. Malondialdehyde is the end product of lipid peroxidation which is an indicator of the extent of lipid peroxidation, while superoxide dismutase is an oxygen free radical scavenger which reflects the antioxidant activity. Furthermore, the expression of transforming growth factor-beta 1 also increases during cardiopulmonary bypass. Transforming growth factor-beta 1 is usually related with the increase of pulmonary endothelial and alveolar epithelial permeability. Additionally, transforming growth factor-beta 1 also leads to decreased sodium channel on the apical surface of alveolar epithelial cells, thus impairing the removal of water and salt for alveolar lumen. Increased oxygen free radicals could activate pro-inflammatory nuclear factors, such as Nuclear factor kappa B and activator protein 1, which lead to upregulation of transforming growth factor-beta 1. Transforming growth factor-beta 1 can reversely promote the expression of oxygen free radicals, thus forming the endless circle of oxygen free radical-transforming growth factor-beta 1-lung injury. All these evidences show that cardiopulmonary bypass use tilts the balance in the lung to pro-inflammatory state which may increase the risk of pulmonary reperfusion injury. ^{Reference Qu, Li, Wang, Yang and Wang48}

The simplest solution to prevent cardiopulmonary bypass-induced pulmonary injury is not using cardiopulmonary bypass in the cardiac surgery (inversion to off-pump operation) as shown in off-pump coronary artery bypass graft surgery. However, it is still impossible to perform most cardiac surgeries without cardiopulmonary bypass. ^{Reference Apostolakis, Koletsis, Baikoussis, Siminelakis and Papadopoulos49} There were some strategies explored to minimise these deleterious effects of cardiopulmonary bypass from improved cardiopulmonary bypass devices and methods to pharmacological pre-conditioning and post-conditioning. However, the effectiveness of these strategies are still unclear. ^{Reference Luc, Aboelnazar and Himmat50–Reference Slottosch, Liakopoulos and Kuhn52}

Cardiopulmonary bypass machines impose patients with very high oxygen tension of 400–500 mmHg. ^{Reference Gauduel, Menasche and Duvelleroy53,Reference Joachimsson, Sjöberg, Forsman, Johansson, Ahn and Rutberg54} Administration of 100% oxygen may cause oxygen toxicity or absorptive atelectasis as shown in a previous study which reported exacerbation of post-operative lung injury with the administration of 100% oxygen during cardiopulmonary bypass. ^{Reference Sasson, Sherman and Ezri55} Therefore, keeping normoxia condition (PO₂ of 80–100 mmHg) of the cardiopulmonary bypass is required to reduce the extent of myocardial and pulmonary dysfunction in regard to reoxygenation injury. ^{Reference Joachimsson, Sjöberg, Forsman, Johansson, Ahn and Rutberg54–Reference Arthur E.Baue, Graeme, Hillel and Keith56}

Aside from hyperoxia, leucocytes might cause reoxygenation injury by generating oxygen-derived radicals. The method of leucocyte depletion strategy by using leucocyte depletion filters may reduce the effect of reoxygenation injury along with keeping the oxygen tension at a normal level. ^{Reference Allen and Ilbawi34} Additionally, in vivo study by Qiu et al reported that reperfused lung tissues increased the expression of enzymatic product inosine monophosphate deaminase which regulates neutrophil trafficking in the microvessel. This finding may provide an alternative prospect for minimising ischaemic-reperfusion-associated lung injury besides the depletion strategy. On the contrary, an ex vivo study by Luc et al showed that there was increased pro-inflammatory cytokines and leucocytes in the perfusate despite the use of leucocyte filter as it became saturated over 12 hours of ex vivo lung perfusion. ^{Reference Luc, Aboelnazar and Himmat50} Therefore, there is still no objective evidence for the routine use of leucocyte filter in cardiopulmonary bypass.

Circuits coating has been used for the prevention of inflammatory reaction in cardiopulmonary bypass use, especially heparin-coated circuit which is the first and most extensively studied. The concept behind heparin coating is mimicking the endothelial surface that contains heparin sulphate, thus reducing complement activation, reducing inflammatory response, and improving clinical outcomes. Most studies showed improved pulmonary function with heparin-coated circuit, but there was no influence on the ICU stay and intubation time of the patients. ^{Reference Apostolakis, Koletsis, Baikoussis, Siminelakis and Papadopoulos49}

A small observational study conducted by Su et al suggested that deep hypothermic circulatory arrest increased the risk of post-operative pulmonary dysfunction compared to that of the deep hypothermic low flow during cardiopulmonary bypass. Although deep hypothermic circulatory arrest confers predisposition to worse hypoxic conditions, longer exposure of blood in the cardiopulmonary bypass circuit during deep hypothermic low flow may lead to more complement-related injury in the pulmonary endothelium, thus exacerbating the risk of lung injury. ^{Reference Qiu, Wada, Stahl and Serhan57}

The use of prime solution in cardiopulmonary bypass circuits may cause increased body fluid volume (hemodilution), thus posing a problem for children who have poor ability to regulate and excrete body fluids content. The excessive increase of body fluids volume may result in haemostatic impairment, coagulation disorders, inflammatory response, and myocardial and pulmonary oedema leading to increased post-operative mortality and morbidity. ^{Reference Hu, Li, Chen, Yan, Zhang and Zhang58} Ultrafiltration is used to minimise hemodilution by removing volume of priming and reducing overall post-operative oedema, specifically that of lungs for better post-operative oxygenation in cardiac surgery. Additionaly, it has been shown that ultrafiltration also removes destructive and inflammatory substances, inflammatory cyokines, and toxin from the circulation as well as increases the colloid oncotic pressure which subsequently prevents the development of pulmonary interstitial oedema. ^{Reference Apostolakis, Koletsis, Baikoussis, Siminelakis and Papadopoulos49}

Both conventional ultrafiltration with or without modified ultrafiltration are used routinely in cardiopulmonary bypass. Conventional ultrafiltration is carried during the running of cardiopulmonary bypass to maintain moderate hemodilution and minimal venous reservoir blood. Modified ultrafiltration, which has greater efficiency in removing excess fluid compared to conventional ultrafiltration, is performed immediately after the termination of cardiopulmonary bypass. Despite its advantage, modified ultrafiltration has some potential disadvantageous such as technical complications, surface-induced inflammatory responses, as well as longer duration and additional cost. ^{Reference Hu, Li, Chen, Yan, Zhang and Zhang58,Reference Kuratani, Bunsangjaroen, Srimueang, Masaki, Suzuki and Katogi59} A meta-analysis of paediatric cardiac surgery showed that conventional ultrafiltration with increased ultrafiltration volume and post-cardiopulmonary bypass haematocrit is compared with conventional ultrafiltration alone. However, modified ultrafiltration did not significantly influence the post-operative aortic occlusion, cardiopulmonary bypass, and hospital stay duration. ^{Reference Hu, Li, Chen, Yan, Zhang and Zhang58} Another meta-analysis of randomised controlled trial of paediatric cardiac surgery also showed that there was significant improvement of clinical conditions in the immediate postbypass period with modified ultrafiltration over conventional ultrafiltration, but the post-operative outcome parameters were not significantly influenced. ^{Reference Kuratani, Bunsangjaroen, Srimueang, Masaki, Suzuki and Katogi59} Therefore, the advantage of conventional ultrafiltration with modified ultrafiltration over conventional ultrafiltration only in children is still unclear.

Steroids have been used as post-operative lung protection after cardiopulmonary bypass for nearly 30 years, but there is still conflicting evidence regarding its effectiveness to reduce post-operative mortality and to improve post-operative complications after cardiopulmonary bypass. ^{Reference Whitlock, Devereaux and Teoh60–Reference Glumac, Kardum and Sodic63} An experimental study showed improvement of post-operative lung function (alveolar-arterial oxygen gradient, pulmonary vascular resistance, and extracellular lung water) by using methylprednisolone as pre-treatment. ^{Reference Lodge, Chai, Daggett, Ungerleider and Jaggers64} However, this was denied by clinical studies by Chaney et al with contradicting results. ^{Reference Chaney, Durazo-Arvizu, Nikolov, Blakeman and Bakhos65,Reference Chaney, Nikolov, Blakeman, Bakhos and Slogoff66} A recent meta-analysis showed that low-dose corticosteroid prophylaxis significantly decreased inflammatory factor concentrations and improved the overall outcome of cardiac surgery with cardiopulmonary bypass in adult patients. However, there was increased risk of myocardial infarction and hyperglycaemia requiring insulin infusion. In children, corticosteroid was associated with shortened cardiopulmonary bypass time, increased risk of insulin infusion, and no substantial changes in mortality and other outcomes. ^{Reference Chai, Zhuang and Tian67} Another review concluded that perioperative corticosteroid did not improve mortality rate or other secondary outcomes such as stroke, renal failure, myocardial infarction, and infection, but there were some benefits: reduced risk of pneumonia and respiratory failure, and shortened length of ICU and hospital stay. ^{Reference Perchermeier and Tassani-Prell68} Despite this contradicting evidence, many centres still use this fast-track recovery protocol as a fundamental strategy. ^{Reference Hall, Smith and Rocker69–Reference Tassani, Richter and Barankay71}

Patent ductus arteriosus stenting

Patent ductus arteriosus stent implantation is a procedure to maintain pulmonary blood flow through the ductus arteriosus, especially in ductal-dependent cyanotic CHD. ^{Reference Fitridge72} This procedure has become more popular as it is minimally invasive, avoiding a median sternotomy or lateral thoracostomy, as well as exposure to cardiopulmonary bypass. ^{Reference Fitridge72,Reference Glatz, Petit and Goldstein73} Glatz et al reported no difference in mortality or unplanned intervention between patent ductus arteriosus stenting and Blalock–Taussig–Thomas shunt. Nevertheless, patent stenting had fewer procedural complications, shorter length of stay and ICU stay, lower diuretic use, and more symmetrical with larger size of pulmonary arteries which are beneficial for primary repair. ^{Reference Glatz, Petit and Goldstein73} Bentham and colleagues also found that patent ductus arteriosus stenting had a significant mortality benefit, less extracorporeal support, fewer ventilation days, shoreter ICU stay, and overall length of stay. ^{Reference Bentham, Zava and Harrison74} These results were generally similar to a study by Nasser et al, though there is no difference in growth and symmetry of pulmonary artery between both groups. ^{Reference Nasser, Abdulrahman, Qwaee, Alakfash, Mohamad and Kabbani75} Despite the aforementioned superiority, patent ductus arteriosus stenting usually required more reintervention with higher rate of failure (17%) which is followed by switching to surgical Blalock–Taussig–Thomas shunt. ^{Reference Bentham, Zava and Harrison74,Reference Nasser, Abdulrahman, Qwaee, Alakfash, Mohamad and Kabbani75} The incidence of pulmonary reperfusion injury in patent ductus arteriosus stenting is rare, but it still may occur as a complication compromising haemodynamic. This is evidenced by a study by Bahaidarah et al founding one case of pulmonary reperfusion injury from 43 patent ductus arteriosus stenting procedures in patients with cyanotic CHD. ^{Reference Bahaidarah, Al-Ata and Alkhushi76,Reference Alwi77}

Right ventricular outflow tract stenting or balloon procedure

Severely desaturated infants with acidosis metabolic who are prostaglandin-dependent in cases of stenotic antegrade pulmonary blood flow as a consequence of the narrowing of the right ventricular outflow tract (infundibular or valvar stenosis) or disturbances in the pulmonary arterial tree such as hypoplastic or the presence of multiple aortopulmonary collateral arteries may require early intervention. Comorbidities such as prematurity, low weight, infection, neurological injury, and other conditions requiring non-cardiac surgery may increase the risk or even delay the primary cardiac repair in neonates. Similarly, Blalock–Taussig–Thomas shunt procedures performed in infants with prematurity, low weight, and hypoplastic pulmonary arteries have increased risk of complications such as pulmonary artery stenosis and pulmonary overcirculation. Hence, this becomes a dillema as these patients are at increased risk of morbidity and mortality for either primary repair bridging treatment of Blalock–Taussig–Thomas shunt. ^{Reference Sandoval, Chaturvedi and Benson2,Reference Castleberry, Gudausky, Berger, Tweddell and Pelech78} Right ventricular outflow tract stenting even becomes the primary palliation procedure for tetralogy of Fallot in some centres. ^{Reference Quandt, Ramchandani and Stickley1}

A few studies reported that right ventricular outflow tract stenting may alleviate both infundibular and pulmonary valve obstruction, increasing oxygen saturation and delaying the requirement for early surgery. This procedure also allowed pulmonary arterial and somatic growth with clinical results comparable to early surgical repair in more favourable patients. ^{Reference Sandoval, Chaturvedi and Benson2,Reference Castleberry, Gudausky, Berger, Tweddell and Pelech78} A systematic review and meta-analysis reported that patients with marked obstruction of pulmonary blood flow, low birth weight, or small pulmonary artery size who underwent right ventricular outflow tract stenting had improved conditions as well as pulmonary blood flow. ^{Reference Laurentius, Wiyono, Dominique Subali and Natalia Siagian79} Similar to other palliative interventions, right ventricular outflow tract has risk of developing pulmonary reperfusion injury after reperfusion of the previously underperfused pulmonary circulation. One study of tetralogy of Fallot patients undergoing right ventricular outflow tract stenting reported 9 out of 12 children (75%) develops post-procedural pulmonary reperfusion injury which mostly resolved in 72 hours. ^{Reference Garcia, Sandoval Jones and Aristizabal Villa80} A review hypothesised that the immediate death observed during early post-operative monitoring of right ventricular outflow tract stenting may be caused by acute respiratory distress syndrome induced by pulmonary reperfusion injury or sepsis. ^{Reference Laurentius, Wiyono, Dominique Subali and Natalia Siagian79} Gradual increment of pulmonary blood flow by redilatation of stent may be required in cases of severe form of tetralogy of Fallot physiology with late presentation to reduce the risk of perioperative death from pulmonary reperfusion injury. ^{Reference Begum, Bhuiyan and Khan81}

Management of acute pulmonary reperfusion injury in post-palliative procedure

Management of pulmonary reperfusion injury post-palliative procedure should focus on diuretics, oxygen, and mechanical ventilatory support until 72 hours. Monitoring should be done in the ICU as titration of diuretics should be done carefully. ^{Reference Bergersen and Lock26} Although conservative fluid management using diuretics in the children has shown to lower mortality rate as well as shorten ICU stay and mechanical ventilation days, the optimal guideline for fluid management in pulmonary reperfusion injury remains controversial. It is due to the heterogeneous nature of population phenotypes with the disease of interest in real-life settings. ^{Reference Lee, Corl and Levy82}

In any chosen mode for ventilatory support, parameter controls must maintain the concept of open-lung ventilation or permissive hypercapnia strategy. This setting would provide a protective effect on the lung, instead of aggravating the lung damage. The recommended adjustment of alveolar protective tidal volume ranges between 4 and 8 mL/kg of ideal weight to prevent unwanted volutrauma. Supplemental oxygen must be adjusted to maintain saturation between 92 and 97%, while ensuring the positive end-expiratory pressure stays below 10 mmHg. ^{Reference Coronado-Muñoz and Escalante-Kanashiro83}

Severe heart failure due to pulmonary overflow is uncommon but may occur if the flow rate is too high thus requiring reduction. This condition may require the use of systemic vasodilator if the systolic blood pressure is above 75 mmHg and diastolic pressure above 30 mmHg. Milrinone may be started from 0.3 to 1 mcg/kg/min in neonates. After milrinone is titrated up to 1 mcg/kg/min, sodium nitroprusside may be started from 0.5 mcg/kg/min and titrated up to 5 mcg/kg/min. ^{Reference Ismail, Almazmi and Khokhar45} Although the concept of bigger shunt size correlating with overshunting is still debatable, minimising overshunting by reducing the shunt size is an option. This may be achieved by replacing the shunt, decreasing the diameter of ductal stent by adding several stents (Russian Doll technique), or increasing the length of tube. Multiple coronary stents would be required to decrease the stent diameter, while increasing the length of the tube can be achieved by using a covered stent. By reducing the diameter and lengthening the duct, this will increase the resistance and decrease the flow rate. ^{Reference Yamashita, Akamine and Sumida84–Reference Dreyer, Mühlfeld and Fehrenbach88}

There are many potential treatments for thetherapy and prevention of pulmonary reperfusion injury based on its complex pathophysiology. Various methods of preconditioning such as ischaemic, hyperthermic, and chemical preconditioning may stimulate the production of heat-shock proteins in the cells which give protective benefits prior to ischaemic reperfusion insult. Therapeutic gases such as nitric oxide, hydrogen, hydrogen sulfide, and carbon monoxide, administration of prostaglandin E1, intravenous injection of soluble complement receptor type 1, administration of platelet-activating factor antagonists, and exogenous surfactant therapy also show potential in prophylaxis and therapy of pulmonary reperfusion injury. All these treatments are still in research, mostly only until in vivo experiments; hence, their clinical evidence remains unelucidated. ^{Reference Yamashita, Akamine and Sumida84–Reference Dreyer, Mühlfeld and Fehrenbach88}